Combination therapy for metastatic breast cancer shows improved survival8 Dec 2016
Progression-free survival (PFS) doubled in patients with aromatase inhibitor-resistant metastatic breast cancer treated with “mTOR inhibitor” everolimus plus fulvestrant as compared with fulvestrant alone, a randomized trial showed.
Increased survival but also side-effects
Results showed a median PFS of 10.4 months with the combination versus 5.1 months with fulvestrant monotherapy.
The efficacy came at a price of increased toxicity, as grade 3+ adverse events occurred more than three times as often with the combination, primarily:
- fatigue, and
However, the safety profile was consistent with observations from a prior randomized trial of everolimus, Noah S. Kornblum, MD, of the Montefiore-Einstein Center for Cancer Care in Bronx, N.Y., said at the San Antonio Breast Cancer Symposium.
"This study provides additional evidence that adding everolimus to antiestrogen therapy in aromatase inhibitor-resistant disease improves clinical outcomes," said Kornblum.
The results were not unexpected, given that both drugs already have FDA approval for estrogen receptor-positive, HER2-negative breast cancer that has demonstrated resistance to aromatase inhibitors, he said.
How does this research relate to recent breast cancer advances?
The trial began before data became available from recently reported studies of the CKD4/6 inhibitors palbociclib and ribociclib, showing unprecedented improvement in PFS in combination with endocrine therapy for advanced HER2-negative breast cancer. Additionally, the combination of everolimus and the nonsteroidal aromatase inhibitor exemestane is already used to treat many women with advanced ER-positive breast cancer.
The everolimus-fulvestrant combination could give clinicians and their patients another option for treating advanced ER-positive, HER2-negative disease. The challenge will be to decide how to sequence the available options to ensure that patients get maximal benefits from treatment, said Kornblum.
Comments from the scientific community
Although the data came from a phase 2 trial, the results can help inform clinical decision making, said Virginia Kaklamani, MD, who moderated a press briefing where Kornblum spoke.
"What is important for clinicians is that, when we use combinations with our patients, there has been some kind of clinical trial that has validated that combination," said Kaklamani, of the University of Texas Health Science Center at San Antonio. "What this clinical trial tells us is that we can use fulvestrant with everolimus clinically. When a patient has been on an aromatase inhibitor and we don't want to use another aromatase inhibitor right after that, then having something else to use is extremely important."
"It seems that for CKD4/6 inhibitors and for everolimus, the sort of endocrine therapy we pair them with is not as important as the fact that we use the drugs," she added. "For us to gain that sort of understanding, we need trials like this one."
Kornblum reported findings from a trial designed, in part, to address the growing issue of aromatase inhibitor resistance in advanced, ER-positive breast cancer. Targeting alternative signaling pathways, such as PI3K-AKT-mTOR with everolimus, offers a possible strategy to overcome the resistance. Pairing everolimus with fulvestrant made sense because the selective estrogen receptor degrader achieves more complete inhibition of ER signaling as compared with other antiestrogens, said Kornblum.
Details of the clinical trial: 130 postmenopausal women
The trial involved 130 postmenopausal women who had a median age of 61. The groups were well balanced with respect to demographic and clinical characteristics, said Kornblum.
All patients received fulvestrant and were randomized to everolimus or placebo. The primary endpoint was PFS, and the trial had the statistical power to detect a 70% improvement in median PFS, from 5.4 months with fulvestrant alone to 9.2 months with the addition of everolimus.
The primary analysis showed that the everolimus-fulvestrant combination was associated with a 40% reduction in the hazard for disease progression or death compared with fulvestrant and placebo.
Grade 3 adverse events occurred in 48% of the fulvestrant-everolimus arm and 14% of the fulvestrant-placebo arm.
The most common grade 3 adverse event associated with everolimus was
- stomatitis, occurring in 9% of patients
- pneumonitis (6%)
- fatigue (5%)
- hyperglycemia (6%).
Kornblum pointed out that the trial design did not incorporate prophylactic use of steroid mouthwash, which has been shown to reduce the frequency and severity of stomatitis in everolimus-treated patients.
Source: MedPage Today